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Expression and Regulation of the Metalloproteinase ADAM-8 during Human Neutrophil Pathophysiological Activation and Its Catalytic Activity on L-Selectin Shedding¹

Maria Gómez-Gaviro^2,*, Maria Domínguez-Luis^2,, Javier Canchado, Jero Calafat, Hans Janssen, Enrique Lara-Pezzi^¶, Anne Fourie^||, Antonio Tugores^#, Agustín Valenzuela-Fernández^**, Faustino Mollinedo, Francisco Sánchez-Madrid^* and Federico Díaz-González^3,

^* Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain; Servicio de Reumatología, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain; Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Salamanca, Spain; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; ^¶ Unidad de Biología Molecular, Hospital de la Princesa, Madrid, Spain; ^|| Johnson & Johnson Pharmaceutical Research and Development, San Diego, CA 92121; ^# Unidad de Investigación, Complejo Hospitalario Materno Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain; and ^** Departamento de Medicina Física y Farmacología, Facultad de Medicina, Universidad de La Laguna, Tenerife, Spain

A disintegrin and metalloproteinase domain (ADAM) proteins are a family of transmembrane glycoproteins with heterogeneous expression profiles and proteolytic, cell-adhesion, -fusion, and -signaling properties. One of its members, ADAM-8, is expressed by several cell types including neurons, osteoclasts, and leukocytes and, although it has been implicated in osteoclastogenesis and neurodegenerative processes, little is known about its role in immune cells. In this study, we show that ADAM-8 is constitutively present both on the cell surface and in intracellular granules of human neutrophils. Upon in vitro neutrophil activation, ADAM-8 was mobilized from the granules to the plasma membrane, where it was released through a metalloproteinase-dependent shedding mechanism. Adhesion of resting neutrophils to human endothelial cells also led to up-regulation of ADAM-8 surface expression. Neutrophils isolated from the synovial fluid of patients with active rheumatoid arthritis expressed higher amounts of ADAM-8 than neutrophils isolated from peripheral blood and the concentration of soluble ADAM-8 in synovial fluid directly correlated with the degree of joint inflammation. Remarkably, the presence of ADAM-8 both on the cell surface and in suspension increased the ectodomain shedding of membrane-bound L-selectin in mammalian cells. All these data support a potential relevant role for ADAM-8 in the function of neutrophils during inflammatory response.

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¹ This work was supported by grants from Ministerio de Ciencia y Tecnología of Spain (SAF02/1634) and Fondo de Investigación Sanitaria (FIS04/1275) (to F.D.-G.) and from Fondo de Investigación Sanitaria (FIS04/0843, FIS01/1048), Fundación de Investigación Médica Mutua Madrileña, Fundación "La Caixa" (BM05-30-0), Junta de Castilla y León (CSI04A05) (to F.M.) F.D.-G. was a recipient of a grant for Research Intensification from Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III. M.G.-G.’s work was supported by a grant from Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III (BEFI 99/0259) and M.D.-L.’s work was supported by a grant from Fundación Rafael Clavijo and Fundación Española de Reumatología.

² M.G.-G. and M.D.-L. have contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Federico Díaz-González, Servicio de Reumatología, Hospital Universitario de Canarias, Ofra s/n. La Cuesta, 38320 La Laguna, Santa Cruz de Tenerife, Spain. E-mail address: jfdiaz{at}huc.canarias.org

⁴ Abbreviations used in this paper: ADAM, a disintegrin and metalloproteinase domain; TACE, TNF--converting enzyme; OCL, osteoclast; RA, rheumatoid arthritis; sADAM, soluble form of ADAM; hADAM, human ADAM; MFI, mean fluorescence intensity; rMFI, relative MFI; sL-selectin, soluble L-selectin; MMP, matrix metalloproteinase.

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